The chemical compound. (2α,5β,7β,10β,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate, which is generically known as “cabazitaxel” is a member of the taxane family. Cabazitaxel is the 7, 10-dimethoxy analogue of docetaxel and like other members of taxane family, it is also a microtubule inhibitor, which is presently approved worldwide, in combination with prednisone, for treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
Cabazitaxel is marketed worldwide under the brand name of JEVTANA® by Sanofi Aventis. JEVTANA® is supplied as a kit consisting of (a) a JEVTANA® injection, which contains 60 mg cabazitaxel in 1.5 mL polysorbate 80; and (b) a diluent, containing approximately 5.7 ml 13% (w/w) ethanol. Prior to administration, the JEVTANA® injection must first be mixed with the diluent, which dilutes the amount of cabazitaxel to 10 mg/ml, and then further diluted into a 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. The concentration of cabazitaxel in the resulting final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
JEVTANA® injection is a micellar formulation. The pre-mix solution is prepared by first dilution in a supersaturated solution by about 400% and is inherently physically unstable. It requires repeated inversions for at least 45 seconds to assure complete mixing of the concentrated drug solution and the diluent. The pre-mix solution, having a concentration of 10 mg of cabazitaxel per mL should be used immediately, preferably within 30 minutes and requires further dilution before administration. Even after second dilution, the concentration of cabazitaxel in the solution remains supersaturated and therefore should be used for intravenous administration immediately, with 8 hours, if stored at room temperature or with 24 hours, if stored under refrigeration conditions. Further, these supersaturated solutions are prone to crystallization and hence the prescribing information for JEVTANA® instructs that if crystals and/or particulates appear in the diluted infusion solution, it must not be used and should be discarded.
Therefore, various attempts have been made to prepare the cabazitaxel formulation with improved properties, however, the lipophilic property and it's practically insolubility in water, having solubility about 8 pg per mL, has vexed researchers in this field.
International Application Publication No. WO 2013/024495 discloses cabazitaxel or a pharmaceutically acceptable salt thereof and at least one solubilizer dissolved in alcoholic solvents.
U.S. Patent Application Publication No. 2012/0065255 discloses a sterile pharmaceutical formulation comprising cabazitaxel which is substantially free of polysorbates and polyethoxylated castor oil. The composition comprises of cabazitaxel or a pharmaceutically acceptable salt thereof; a solubilizer, tocopherol polyethylene glycol succinate, one or more hydrotropes and optionally one or more agents having a pa of about 3 to about 6 and optionally one or more antioxidizing agent.
U.S. Patent Application Publication No. 2014/0171495 discloses an enclosed liquid pharmaceutical composition container, comprising a liquid phase and a gaseous phase, wherein the liquid phase comprises cabazitaxel, polysorbate 80, ethanol, and one or more pH adjusters to maintain pH about 2.8-6.0, and the gaseous phase is saturated with CO2.
U.S. Pat. No. 7,241,907 discloses a process for preparing an acetone solvate of cabazitaxel by crystallization from an aqueous acetone solution and for use of the same in preparing pharmaceutical composition.
Thus, there remains a need for a stable, single-vial formulation for cabazitaxel, which needs to be diluted only once for intravenous infusion. Ideally, such formulations would be conveniently prepared for use and would exhibit enhanced storage stability at ambient conditions.